ARTICLE: Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study
AUTHORS: Akshay N Gupte, Pavan Kumar, Mariana Araújo-Pereira, Vandana Kulkarni, Mandar Paradkar, Neeta Pradhan, Pradeep Menon, Chandrasekaran Padmapriyadarsini, Luke-Elizabeth Hanna, Shri Vijay Bala Yogendra Shivakumar, Neesha Rockwood, Elsa Du Bruyn, Rajesh Karyakarte, Sanjay Gaikwad, Robert Bollinger, Jonathan Golub, Nikhil Gupte, Vijay Viswanathan, Robert J Wilkinson, Vidya Mave, Subash Babu, Hardy Kornfeld, Bruno B Andrade, Amita Gupta
JOURNAL: Eur Respir J. 2022 Apr 21;59(4):2100905. doi: 10.1183/13993003.00905-2021. Print 2022 Apr.
Background: Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear.
Methods: We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively.
Results: Pre-treatment interferon-γ, interleukin (IL)-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95% CI 1.08-4.33; p=0.02), recurrence (aOR 5.36, 95% CI 2.48-11.57; p<0.001) and death (aOR 4.62, 95% CI 1.95-10.95; p<0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15% (C-statistic 0.66 versus 0.76; p=0.02).
Conclusions: Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction.
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